Results In February 2004, after reviewing data through November 30, 2003, the
National Institutes of Health (NIH) decided to end the intervention phase
of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals
[CIs]) for CEE vs placebo for the major clinical outcomes available through
February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12)
with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39
(1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal
cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91)
with 102 cases. Corresponding results for composite outcomes were: total cardiovascular
disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures,
0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index,
1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was
an absolute excess risk of 12 additional strokes per 10 000 person-years
and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years.
The estimated excess risk for all monitored events in the global index was
a nonsignificant 2 events per 10 000 person-years.

Conclusions The use of CEE increases the risk of stroke, decreases the risk of hip
fracture, and does not affect CHD incidence in postmenopausal women with prior
hysterectomy over an average of 6.8 years. A possible reduction in breast
cancer risk requires further investigation. The burden of incident disease
events was equivalent in the CEE and placebo groups, indicating no overall
benefit. Thus, CEE should not be recommended for chronic disease prevention
in postmenopausal women.

Estrogen therapy has been available to postmenopausal women for more
than 60 years. Proven benefits include relief of vasomotor symptoms and vaginal
atrophy and prevention and treatment of osteoporosis. Observational studies
primarily examining unopposed estrogen preparations have suggested a 30% to
50% reduction in coronary events,1- 3 and
an 8% to 30% increase in breast cancer with extended use.4- 6

The Women's Health Initiative (WHI) clinical trials of hormone therapy
were designed in 1991-1992 using the accumulated evidence available at the
time.7 Two parallel randomized, double-blind,
placebo-controlled clinical trials of hormone therapy were undertaken to determine
whether conjugated equine estrogen (CEE) alone (for women with prior hysterectomy)
or in combination with progestin (medroxyprogesterone acetate [MPA]) would
reduce cardiovascular events in mostly healthy postmenopausal women. The WHI
estrogen plus progestin trial was halted in July 2002 after a mean 5.2 years
of follow-up because health risks exceeded benefits.8 Coronary
heart disease (CHD), stroke, and venous thromboembolic disease were all increased
in women assigned to active treatment with estrogen plus progestin. Breast
cancer was also increased while colorectal cancer, hip fracture, and other
fractures were reduced. The lack of benefit for CHD was supported by the Heart
and Estrogen/progestin Replacement Study (HERS), which also tested CEE plus
MPA in women with known coronary artery disease at baseline.9

Despite the early termination of the WHI estrogen plus progestin trial,
the WHI estrogen-alone trial was continued with ongoing careful scrutiny by
an independent data and safety monitoring board (DSMB) because the health
risks and benefits had not been adequately determined. In February 2004, the
National Institutes of Health (NIH) decided to terminate the intervention
phase of the estrogen-alone study, prior to the scheduled close-out interval
of October 2004 to March 2005. This report presents the results of the estrogen-alone
trial using available data through February 29, 2004, prior to notifying participants
of the decision on March 1, 2004. Subsequent detailed reports will include
additional outcomes occurring between the participants' last routine follow-up
and the date of trial termination. An ancillary study of dementia and cognitive
function will be reported separately. Two remaining components of the WHI
clinical trial, testing the effects of a low-fat eating pattern and, independently,
the effects of calcium plus vitamin D supplementation, are continuing.

Methods

Study Population and Randomization

Detailed eligibility criteria and recruitment methods have been published.7,10 Briefly, most participants were recruited
by population-based direct mailing campaigns to age-eligible women, in conjunction
with local and national media awareness programs. Women were eligible if they
were 50 to 79 years old at initial screening, had undergone hysterectomy (thereby
considered postmenopausal for enrollment purposes), and were likely to reside
in the area for 3 years. Major exclusions were related to competing risks
(any medical condition likely to be associated with a predicted survival of
<3 years), safety (eg, prior breast cancer, other prior cancer within the
last 10 years except nonmelanoma skin cancer), adherence and retention concerns
(eg, alcoholism, dementia, and transportation problems), or the clinical judgment
of the participant's health care practitioner to continue hormone therapy
in symptomatic or osteoporotic women. A 3-month washout period was required
of women using postmenopausal hormones at initial screening. Prior to the
1997 HERS report,11 which led to a change in
eligibility criteria, 171 women with a history of venous thromboembolism (VTE)
were enrolled. The protocol and consent forms were approved by the institutional
review board for each participating institution (see the end of this article),
and all women provided written informed consent.

Eligible women were randomly assigned to receive 0.625 mg/d of CEE (Premarin;
Wyeth, St Davids, Pa) or a matching placebo, in equal proportions. The computerized
randomization and blinding procedures have been described.12 A
small imbalance in the number of women in each group was a consequence of
an early protocol change eliminating a CEE-alone intervention in women with
a uterus.8

Follow-up and Data Collection

Study participants were contacted by telephone 6 weeks after randomization
to assess symptoms and reinforce adherence. Follow-up contacts by telephone
or clinic visit occurred every 6 months, with clinic visits required annually.
At each contact, adherence to study medication was assessed, and information
on symptoms, safety concerns, and outcomes was collected. Electrocardiograms
were recorded at baseline and at visit years 3, 6, and 9. Annual mammograms
and clinical breast examinations were required; study medication was withheld
if these safety procedures were not performed or the results could not be
verified. Participants were followed up from the date of entry until death,
loss to follow-up, or the time of a request for no further contact, regardless
of their adherence to study medication. Baseline and year 1 lipid levels were
measured in fasting blood specimens from a random 8.6% subsample of women.
Methods for subsampling, data collection and management, and quality assurance
have been published.12

Maintenance/Discontinuation of Study Medications

During the trial, women with intolerable symptoms such as breast tenderness
were managed by reducing the number of days per week that study medication
was taken. Participants and study personnel remained blinded when these adjustments
were made. Study medication was withheld in participants experiencing a myocardial
infarction (MI), stroke, fracture or major injury involving hospitalization,
surgery involving use of anesthesia, any illness resulting in immobilization
for longer than 1 week, or any other severe illness in which hormone use was
considered inappropriate. The decision to resume study medication after MI
or stroke was left to the discretion of the clinical center, individual participant,
and her health care clinician. Study medication was permanently discontinued
in women who developed breast cancer; deep vein thrombosis (DVT) or pulmonary
embolism (PE); malignant melanoma; meningioma; triglyceride level higher than
1000 mg/dL (>11.3 mmol/L); or who were treated by their personal health care
practitioners with prescription estrogen, testosterone, or selective estrogen
receptor modulators.

Outcome Ascertainment

Designated outcome events were evaluated by review of medical records
by centrally trained physician adjudicators at each clinical center who were
blinded to treatment assignment and symptoms related to study medication.
Final adjudication of key cardiovascular and cancer outcomes, as well as hip
fractures and deaths, was performed centrally by comparably blinded WHI physician
adjudicators, neurologists, or cancer coders. Centrally adjudicated results
are reported when available, with locally adjudicated events included when
central adjudication has not yet been completed. Centrally adjudicated results
are available for 95.7% of CHD events, 92.4% of strokes, 91.8% of PE cases,
97.2% of breast cancers, 99.2% of colorectal cancers, 89.2% of hip fractures,
and 80.3% of deaths. Detailed outcome definitions and methods for ascertaining,
documenting, and classifying outcomes have been published.13

Cancer. All cancers other than nonmelanoma
skin cancers were confirmed by pathology reports, available for 98.2% of invasive
breast, 95.0% of colorectal, and 80.6% of other cancers.

Fractures. All reported clinical fractures
other than those of the ribs, chest/sternum, skull/face, fingers, toes, and
cervical vertebrae were verified by review of radiology, MRI, or operative
reports. WHI investigators did not obtain spine radiographs to ascertain subclinical
vertebral fractures.

Global Index. A global index of risks and benefits
was defined for each woman as the time to the first event among the monitored
outcomes (CHD, stroke, PE, breast cancer, colorectal cancer, hip fractures,
and death).14

Statistical Power and Analyses

The trial design assumed 12 375 women would need to be randomized
to achieve 81% power to detect a 21% reduction in CHD rates over the projected
9-year average follow-up. This sample size would provide 65% power to detect
a 20% reduction in hip fracture rates. An additional 5 years of follow-up
without intervention was planned to achieve 79% power to detect a 22% increase
in breast cancer risk.7 Calculations based
on the observed sample size and age distribution gave power estimates of 72%,
55%, and 71% for CHD, hip fracture, and breast cancer, respectively.12

Lack of adherence to study medication was summarized at each follow-up
year as the cumulative proportion of randomized participants who had stopped
taking study medications (dropouts) and similarly the proportion of women
who began taking prescription menopausal hormones through their own health
care practitioner (drop-ins), after excluding preceding deaths. Participants
were classified by their most recent status with regard to study medications
(stopped or not). Thus, women who temporarily stopped taking study medication
were considered adherent in this analysis.

Event rate comparisons were based on the intent-to-treat principle using
failure time methods. For a given outcome, the time of event was defined to
be the number of days from randomization to the first postrandomization diagnosis
of the designated event. For silent MIs, the date of the follow-up electrocardiogram
was used as the event date. Follow-up time was censored at the time of the
last documented follow-up contact or death. Comparisons of primary outcomes
are presented as hazard ratios (HRs) and 95% confidence intervals (CIs) from
Cox proportional hazard analyses,15 stratified
by age, prior disease, and randomization status in the low-fat diet trial.
Cumulative hazard rates were estimated by the Kaplan-Meier method for each
designated outcome.

Two forms of CIs were calculated, nominal and adjusted. This report
primarily presents the nominal 95% CIs because they provide traditional estimates
of variability and, as such, are comparable to most other reports of hormone
therapy studies. To acknowledge multiple testing issues, adjusted CIs were
calculated using group sequential methods, and for secondary outcomes a Bonferroni
correction based on the data and safety monitoring plan (see below). Because
the trial was nearing the planned termination, the impact of the group sequential
adjustment on the width of the CIs is small. The Bonferroni correction reflects
the study design and trial monitoring priorities and hence may be somewhat
less relevant for interpreting the trial results. Unless otherwise indicated,
all CIs and P values are nominal. Statistical analyses
were performed using SAS version 9.0 (SAS Institute, Cary, NC) and significance
was set at the .05 level.

The possibility of important subgroup effects was explored by testing
for interactions in expanded Cox models. Because 23 interactions are reported,
chance alone could produce a significant interaction at the .05 level for
approximately 1 factor in the series. Sensitivity analyses were conducted
to explore the possible impact of lack of adherence to study medications.
In these "complier" analyses, the randomization assignment was preserved but
follow-up for a woman was censored 6 months after she first became nonadherent
(defined as taking <80% of study pills).

Data and Safety Monitoring

Statistical monitoring boundaries were based on O'Brien-Fleming group
sequential procedures16 with asymmetric boundaries
for benefit (1-sided .025-level upper boundary for CHD) and adverse effects
(1-sided .05-level lower boundary). The adverse effect boundary for the 6
monitored outcomes of CHD, stroke, PE, hip fractures, colorectal cancer, and
death from causes other than the monitored disease outcomes incorporated a
Bonferroni correction. The Bonferroni correction was not applied to breast
cancer because it was the primary safety outcome. Early stopping was to be
considered if a disease-specific boundary was crossed and the global index
was supportive of the overall direction of CEE effects. Formal monitoring
of disease rate comparisons began in the fall of 1997 with trial termination
planned for March 2005. Additional aspects of the monitoring plan have been
published.14

Results

Trial Monitoring and Early Stopping

In early 2000 and again in 2001, after reviewing the data from the estrogen-alone
and the estrogen plus progestin trials, the DSMB recommended that participants
in both trials be informed of early increases in rates of heart disease, strokes,
and blood clots in women taking active hormone pills. In 2002, with the early
termination of the estrogen plus progestin trial, participants in the estrogen-alone
trial were informed that no increase in breast cancer rates had been observed
at that point in women taking CEE. The DSMB continued to closely monitor the
estrogen-alone trial. The DSMB's review of the data for the 13th planned interim
analysis through August 31, 2003, plus an unplanned analysis using data through
November 30, 2003, did not lead to a consensus recommendation. None of the
predefined stopping boundaries had been crossed, although the stroke comparison
was approaching the adverse effect boundary.

On February 2, 2004, following subsequent reviews with additional advisors,
the NIH decided to stop the intervention phase of the trial. The NIH concluded
that with an average of nearly 7 years of follow-up completed, CEE does not
appear to affect the risk of heart disease, the primary outcome of the study.
Furthermore, the NIH found an increased risk of stroke that was similar to
the risk reported from the estrogen plus progestin trial. Recognizing the
risk of stroke, and the likelihood that neither cardioprotection nor breast
cancer risk would be demonstrated in the remaining intervention period, the
NIH deemed it unacceptable to subject healthy women in a prevention trial
to this risk.17 On March 1, 2004, participants
were informed of the trial termination and advised to stop taking their study
medication. Data available through February 29, 2004, by routine data collection
are included in this report.

Baseline Characteristics

Between 1993 and 1998, a total of 10 739 women were randomized
into the estrogen-alone trial. Demographic characteristics, medical history,
and health behaviors of these women have been described in considerable detail.18 In general, study participants were healthy and at
average risk of CHD and breast cancer, although 441 (4.1%) with prior MI or
coronary revascularization were enrolled. The intervention groups were well
balanced at baseline on key demographic and disease risk factor characteristics
(Table 1 and Table 2).

Follow-up, Adherence, and Unblinding

Vital status is known for 10 176 (94.8%) of randomized participants,
including 580 (5.4%) known to be deceased. Over the average 6.8 years of follow-up
(range, 5.7-10.7 years), only 563 women (5.2%) withdrew, were considered lost
to follow-up, or had stopped providing outcomes information for more than
18 months (Figure 1).

At the time of study termination, 53.8% of women had already stopped
taking study medication. Dropout rates exceeded design projections, particularly
early on, but did not differ significantly by randomization assignment and
were stable after year 1, even with the termination of the estrogen plus progestin
trial (Figure 2). Some women initiated
hormone use through their own health care clinician: 5.7% of women in the
CEE group and 9.1% in the placebo group by follow-up year 6. These drop-in
rates in the placebo group were also somewhat greater than expected. Reasons
for initiating hormone therapy outside of the study were not captured. Unblinding
of the study gynecologist to randomization assignment was infrequent, occurring
for only 100 women in the CEE group and 83 in the placebo group. Per protocol,
the treatment assignment was not revealed to other study staff members or
the study participants.

Intermediate Cardiovascular Disease End Points

Fasting blood lipid levels, assessed in an 8.6% subsample of women at
baseline and year 1, showed a greater reduction in low-density lipoprotein
cholesterol (−13.7% vs –1.0%, P<.001)
and a larger increase in high-density lipoprotein cholesterol (15.1% vs 1.1%, P<.001) in the CEE group compared with the placebo group.
Reductions in total cholesterol from baseline to year 1 were comparable (−2.3%
vs −1.4%, P = .41). Larger increases in triglyceride
levels at year 1 were observed in the CEE group than in the placebo group
(25.0% vs 3.0%, P<.001). Systolic blood pressure
at 1 year was higher by a mean (SE) of 1.1 (0.4) mm Hg in women taking CEE
than in women taking placebo (P = .003) and remained
similarly elevated throughout follow-up. Diastolic blood pressures did not
differ significantly between the study groups (data not shown).

Clinical Outcomes

Cardiovascular Disease. The primary outcome
for this trial was the rate of CHD. The observed CHD incidence rate of 51
per 10 000 person-years was 15% lower than projected in the design. No
significant effect of CEE was observed on CHD rates compared with placebo
(49 vs 54 per 10 000 person-years; 9% reduction) (Table 3). These data rule out a reduction in CHD rates with CEE
of more than 25% during the trial period. The incidence of stroke was increased
by 39% in the CEE group (44 vs 32 per 10 000 person-years, z = −2.72, P = .007), which crossed
the adverse effect monitoring boundary for the 14th planned interim analysis
(defined as z = −2.69). The risk of VTE, including
both DVT and PE, was increased for women taking CEE (28 vs 21 per 10 000
person-years; 33% increase), although only the increased rate of DVT reached
statistical significance (P = .03). Total cardiovascular
disease event rates, including stroke, were 12% higher in women taking CEE
(225 vs 201 per 10 000 person-years, P = .02).

Cancer. Invasive breast cancer, the primary
safety outcome for this trial, was diagnosed at a 23% lower rate in the CEE
group than in the placebo group (26 vs 33 per 10 000 person-years) and
this comparison narrowly missed statistical significance (P = .06). No significant differences were found in rates of colorectal
cancer for CEE vs placebo (17 vs 16 per 10 000 person-years) or total
cancer (103 vs 110 per 10 000 person-years) (Table 3).

Summary Measures. The global index of health
risks and benefits was balanced overall (HR, 1.01; 95% CI, 0.91-1.12). Of
the 580 reported deaths, 94.8% have been adjudicated. Use of CEE did not significantly
affect total mortality rates or cause-specific mortality (Table 4).

Time Trends

Differences in cumulative hazards for stroke and to a lesser extent
for hip fracture began to emerge early in the intervention period and persisted
throughout follow-up (Figure 3).
Cumulative breast cancer hazard rates appeared to separate beginning in year
2. Similar displays for the global index and death (Figure 4) reinforce the comparability of these rates across treatment
groups. Tests for trends with time since randomization were computed for all
of the monitored and composite outcomes using a Cox proportional hazards model
with a time-dependent treatment interaction term. Coronary heart disease was
the only outcome with a statistically significant trend (P = .02) of slightly elevated HRs in the early follow-up period that
diminished over time (year 1, 1.16; year 2, 1.20; year 3, 0.89; year 4, 0.79;
year 5, 1.28; year 6, 1.24, and year ≥7, 0.42).

Further Analyses

Exploratory analyses were conducted to determine whether selected participant
characteristics modified CEE effects on major clinical outcome event rates.
There were no significant interactions between CEE and race/ethnicity or body
mass index on risk of CHD, stroke, VTE, breast cancer, colorectal cancer,
hip fracture, or total osteoporotic fracture (data not shown). Of particular
interest for all outcomes was age at enrollment (Figure 5). The only treatment × age interaction reaching statistical
significance was for colorectal cancer (P = .048),
for which increasing age was associated with increasing risk with CEE use.

The effect of prior disease on cardiovascular event rates was also evaluated.
Among the 441 women enrolled with prior MI or revascularization procedures,
the effect of CEE relative to placebo (33 vs 31; HR, 1.04; 95% CI, 0.63-1.71)
did not differ significantly from the CEE effect in women without documented
CHD (143 vs 162; HR, 0.91; 95% CI, 0.73-1.14) (P =
.55). Similarly, in 168 women reporting prior stroke, the HR for subsequent
stroke (6 vs 6; HR, 1.67; 95% CI, 0.52-5.36) did not differ from the HR in
women without a history of stroke (152 vs 112; HR, 1.39; 95% CI, 1.09-1.78)
(P = .77). Removing from analysis the few participants
with a history of PE did not alter the hazard ratio for PE substantially (47
vs 37; HR, 1.31; 95% CI, 0.85-2.01).

The WHI estrogen-alone study was a large-scale, randomized, double-blind,
placebo-controlled trial designed to test the effects of the most commonly
used postmenopausal hormone therapy preparation in the United States19 on chronic disease incidence in a diverse population
of mostly healthy postmenopausal women aged 50 to 79 years. As conceived,
the study had adequate power to detect moderate effects on CHD, hip fractures,
and with longer-term follow-up, breast cancer among women across the broad
age range relevant for disease prevention hypotheses. This trial demonstrated
that CEE increases the risk of stroke, reduces the risk of hip and other fractures,
but does not significantly affect the incidence of CHD (the primary outcome)
or overall mortality. A nonsignificant reduction in breast cancer incidence
requires additional investigation. These observed risks and benefits of CEE
for chronic disease rates appear to be balanced over an average 6.8-year follow-up
period.

The lack of effect of CEE on CHD risk is substantially different from
the favorable reports from observational studies that motivated this trial,
and was observed despite an improvement in cholesterol levels. However, these
results are consistent with several recent secondary prevention trials that
showed no benefit of hormone therapy on atherosclerosis or clinical events.20- 24 The
current study suggests that younger women who use CEE may be at reduced risk
of CHD but this possible association may be due to chance.

These CHD results for CEE also differ importantly from 2 previous trials
of estrogen plus progestin. In both the WHI estrogen plus progestin trial25 and HERS,26 the risk
of CHD was significantly elevated in the first year of treatment and the cumulative
effects of estrogen plus progestin never appeared beneficial. In the current
study, a smaller, nonsignificant increase was observed in the first year of
CEE exposure but the cumulative effect suggests a possible modest benefit
with longer-term use. Potential explanations for this discrepancy include
the role of progestin, differences in the study populations in baseline risk
factors,18 duration of intervention and follow-up
time, and the role of chance.

The observed adverse effect of CEE on the risk of stroke is consistent
with the risks reported by the WHI and HERS estrogen plus progestin trials.27,28 In addition, the use of estradiol
in women after ischemic stroke resulted in no change in mortality but a higher
rate of recurrent nonfatal stroke and a suggestion of more severe functional
deficits.29 The small but persistent increase
in systolic blood pressure in women taking CEE is one possible contributor
to this effect because relatively small differences in systolic blood pressure
have been positively associated with differences in stroke and cardiovascular
disease rates.30,31

The WHI estrogen-alone trial provides strong evidence that CEE reduces
the risk of hip, clinical vertebral, and other fractures. These reductions
were of similar magnitude to those observed in the WHI estrogen plus progestin
trial32 and are consistent with findings from
prior observational studies33,34 and
recent meta-analyses.35- 37

The trend toward a reduction in breast cancer incidence was unanticipated
and is opposite of that observed in the WHI estrogen plus progestin trial,
which reported a 24% increased risk.38 These
results also appear contrary to the preponderance of observational study results,4,39 including those from the recent Million
Women Study.40 When examining breast cancer
risk by type of hormone therapy, most of these studies have reported a modest
increase in breast cancer risk with estrogen alone but a greater risk for
estrogen plus progestin. Still others have recently found little or no effect
of estrogen alone on breast cancer risk.41 Differences
in breast cancer screening between the CEE and placebo groups do not explain
the observed breast cancer effects because the WHI protocol mandated annual
mammography and clinical breast examinations. The possibility that diagnostic
delay could account for this reduction seems remote because the effect of
CEE alone on breast density is minimal.42 Longer-term
effects of CEE on breast cancer risk remain uncertain. Extended follow-up,
as is currently planned, and analyses of breast cancer characteristics similar
to those reported for the estrogen plus progestin study38 may
provide additional insight.

In preliminary subgroup analyses, the estimated HRs for CEE for several
monitored outcomes, including the global index, were lower for women aged
50 to 59 years, although differences in HRs across age groups were not statistically
significant. While these results suggest that CEE may be somewhat more favorable
in younger than in older women, these subgroup analyses must be interpreted
with caution; we cannot exclude the role of chance or limited power.

Limitations

This trial was designed to test only one unopposed estrogen preparation
at a single dose, administered orally. We cannot determine whether these results
would apply to other formulations, doses, or routes of administration. Care
is needed in making comparisons of these estrogen-alone trial results to those
of the estrogen plus progestin trial, even though this is of considerable
interest. The differences between these 2 study populations in their baseline
characteristics,18,43 their event
rates, the length of intervention and follow-up time, and the completeness
of data at this initial report are sufficient to make simple contrasts potentially
misleading. More detailed analyses of these parallel trials are planned.

The high rates of discontinuation of study medications and higher than
expected crossover from placebo to active hormone use are further limitations.
The rate of discontinuation is less than what is usually observed in clinical
practice44 and was similar in the 2 groups.
The somewhat higher drop-in rate in the placebo group is not explained by
unblinding, which was infrequent (1.5%) and similar in the 2 groups. Sensitivity
analyses suggest that the lack of adherence to assigned study medication may
have diluted the CEE effects, both positive and negative, relative to what
might be observed with full adherence, but it did not distort the overall
balance of effects.

Lower than anticipated event rates for some outcomes, particularly CHD
and hip fractures, reduce the power relative to what was originally projected
but reinforce the generally healthy status of these participants. The fact
that the trial was stopped early further decreases the precision of the estimated
effects. A longer intervention period may have provided stronger statistical
evidence of CEE effects, particularly for CHD, for which some evidence of
a trend with time was observed, and for breast cancer, for which the cumulative
effect of long-term exposure remains uncertain. Additional data could have
allowed for more informative subgroup analyses. Extended follow-up of these
women without further intervention is planned.

Clinical Implications

In women aged 50 to 79 years reporting a prior hysterectomy, CEE did
not affect CHD rates but did increase the risk of stroke, accounting for an
excess risk of 12 cases per 10 000 person-years, and reduced the risk
of hip fractures, resulting in 6 fewer cases per 10 000 person-years.
Unexpectedly, women taking CEE also appeared to be diagnosed as having breast
cancer at a lower rate than women taking placebo, but the estimated 7 fewer
cases per 10 000 person-years did not reach statistical significance.
The totality of monitored effects, as summarized in the prespecified global
index, suggests an overall balance of risks and benefits and importantly no
effect on total mortality.

Based on these findings, women and their health care professionals now
have usable risk estimates for the benefits and harms of CEE alone. Women
considering taking CEE should be counseled about an increased risk of stroke
but can be reassured about no excess risk of heart disease or breast cancer
for at least 6.8 years of use. At present, these data demonstrate no overall
benefit of CEE for chronic disease prevention in postmenopausal women and
thus argue against its use in this setting. Overall, these data support the
current US Food and Drug Administration recommendations for postmenopausal
women to use CEE only for menopausal symptoms at the smallest effective dose
for the shortest possible time.45